Epidemiological studies suggest that Asian Indians are insulin resistant and at increased risk for diabetes and cardiovascular disease. Studies by our group and others have demonstrated that, compared to Caucasians matched for body mass index (BMI) and age, Asian Indians were more insulin resistant, had altered body composition, and had increased levels of several markers for cardiovascular risk. Furthermore, we have shown more recently that healthy non-diabetic Asian Indians have significant impairment in insulin-mediated vasodilation, the magnitude of which was significantly correlated with the severity of insulin resistance.Vascular dysfunction plays an integral part in the insulin resistance syndrome and can contribute to atherosclerosis and CAD. Based on the principles derived from basic vascular biology, techniques like brachial artery ultrasound and contrast enhanced ultrasound can be used to better understand the hemodynamic actions of insulin on the vasculature, thereby enabling us to understand the relationship between vascular reactivity and glucose uptake in skeletal muscle. This grant proposal focuses on insulin's action on both bulk and microvascular perfusion, and their relation to glucose metabolism in insulin resistant non-diabetic Asian Indians. The primary goal of this project is to assess if physiological levels of insulin enhance microvascular perfusion in human skeletal muscle by capillary recruitment, using the technique of contrast-enhanced ultrasound. We expect to see dissociation between insulin's action on capillary recruitment and total blood flow. Specifically, we hypothesize that insulin's action on capillary recruitment occurs earlier than changes in blood flow, and that there is a direct relationship between capillary recruitment and insulin's ability to stimulate glucose uptake in the skeletal muscle. Our second goal is to determine if healthy Asian Indians have blunted capillary recruitment that is related to their decreased insulin sensitivity. Healthy Asian Indian and Caucasians matched for BMI and age will undergo a hyperinsulinemic euglycemic clamp, and will have capillary recruitment and brachial artery blood flow measured at baseline, and after 30 and 120 minutes of hyperinsulinemia to assess the temporal relationship between vascular reactivity and glucose uptake. We anticipate that physiological doses of insulin will increase capillary recruitment and glucose uptake before its effect on increasing total blood flow occurs. We hypothesize that insulin resistant Asian Indians will have blunting of capillary recruitment, and that there will be a significant correlation between the magnitude of the blunting and the reduction in glucose uptake by the skeletal muscle compared to Caucasians. The results of our investigation will help us to move towards conducting studies exploring the sites and mechanisms of action of insulin in the vasculature, and to determine whether insulin sensitizers improve insulin resistance by increasing capillary recruitment leading to enhanced skeletal muscle glucose uptake.